Researchers build most complex synthetic biology circuit yet

Oct 08, 2012 by Anne Trafton

MIT biological engineers created new genetic circuits using genes found in Salmonella (seen here) and other bacteria. Credit: NIH

Using genes as interchangeable parts, synthetic biologists design cellular circuits that can perform new functions, such as sensing environmental conditions. However, the complexity that can be achieved in such circuits has been limited by a critical bottleneck: the difficulty in assembling genetic components that don't interfere with each other.

Unlike electronic circuits on a silicon chip, biological circuits inside a cell cannot be physically isolated from one another. "The cell is sort of a burrito. It has everything mixed together," says Christopher Voigt, an associate professor of biological engineering at MIT.

Because all the cellular machinery for reading genes and synthesizing proteins is jumbled together, researchers have to be careful that proteins that control one part of their synthetic circuit don't hinder other parts of the circuit.

Voigt and his students have now developed circuit components that don't interfere with one another, allowing them to produce the most complex synthetic circuit ever built. The circuit, described in the Oct. 7 issue of Nature, integrates four sensors for different molecules. Such circuits could be used in cells to precisely monitor their environments and respond appropriately.

"It's incredibly complex, stitching together all these pieces," says Voigt, who is co-director of the Synthetic Biology Center at MIT. Larger circuits would require computer programs that Voigt and his students are now developing, which should allow them to combine hundreds of circuits in new and useful ways.

Expanding the possibilities

Previously, Voigt has designed bacteria that can respond to light and capture photographic images, and others that can detect low oxygen levels and high cell density—both conditions often found in tumors. However, no matter the end result, most of his projects, and those of other synthetic biologists, use a small handful of known genetic parts. "We were just repackaging the same circuits over and over again," Voigt says.

To expand the number of possible circuits, the researchers needed components that would not interfere with each other. They started out by studying the bacterium that causes salmonella, which has a cellular pathway that controls the injection of proteins into human cells. "It's a very tightly regulated circuit, which is what makes it a good synthetic circuit," Voigt says.

The pathway consists of three components: an activator, a promoter and a chaperone. A promoter is a region of DNA where proteins bind to initiate transcription of a gene. An activator is one such protein. Some activators also require a chaperone protein before they can bind to DNA to initiate transcription.

The researchers found 60 different versions of this pathway in other species of bacteria, and found that most of the proteins involved in each were different enough that they did not interfere with one another. However, there was a small amount of crosstalk between a few of the circuit components, so the researchers used an approach called directed evolution to reduce it. Directed evolution is a trial-and-error process that involves mutating a gene to create thousands of similar variants, then testing them for the desired trait. The best candidates are mutated and screened again, until the optimal gene is created.

Aindrila Mukhopadhyay, a staff scientist at Lawrence Berkeley National Laboratory, says the amount of troubleshooting the researchers did to create each functional module is impressive. "A lot of people are charmed by the idea of creating complex genetic circuits. This study provides valuable examples of the types of optimizations that they may have to do in order to accomplish such goals," says Mukhopadhyay, who was not part of the research team.

Layered circuits

To design synthetic circuits so they can be layered together, their inputs and outputs must mesh. With an electrical circuit, the inputs and outputs are always electricity. With these biological circuits, the inputs and outputs are proteins that control the next circuit (either activators or chaperones).

These components could be useful for creating circuits that can sense a variety of environmental conditions. "If a cell needs to find the right microenvironment—glucose, pH, temperature and osmolarity [solute concentration]—individually they're not very specific, but getting all four of those things really narrows it down," Voigt says.

The researchers are now applying this work to create a sensor that will allow yeast in an industrial fermenter to monitor their own environment and adjust their output accordingly.

Through the assembly of genetic components into "circuits" that perform logical operations in living cells, synthetic biologists aim to artificially empower cells to solve critical problems in medicine, energy ...

For about a dozen years, synthetic biologists have been working on ways to design genetic circuits to perform novel functions such as manufacturing new drugs, producing fuel or even programming the suicide ...

(PhysOrg.com) -- A single cell in the human body is approximately 10,000 times more energy-efficient than any nanoscale digital transistor, the fundamental building block of electronic chips. In one second, ...

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protein folding is just how a protein literally folds up when placed in water. the exposed surface of the folded protein is what does the 'job' ... the protein's circuit abilities are literally on its exposed surface.

synthetic life based on salmonella, genetically modified food with e. coli genes spliced into it, etc. etc. etc. It's over for homo sapiens. in about 100 more years we not only will have destroyed the ecosystem but also our own species, because we were too foolish not to. zombies raised in captivity (and the people who vote for them) do not think twice before shooting to kill. and this report was in the journal Nature? LOL... other than the fact that nature is incompatible with humans who think they can play god, what does nature have to do with any of that? nothing.

I was going to write a serious reply to this but then I noticed your username and realized you are only here to promote your agenda so I think I'll just say the following:

Fuck You.

synthetic life based on salmonella, genetically modified food with e. coli genes spliced into it, etc. etc. etc. It's over for homo sapiens. in about 100 more years we not only will have destroyed the ecosystem but also our own species, because we were too foolish not to. zombies raised in captivity (and the people who vote for them) do not think twice before shooting to kill. and this report was in the journal Nature? LOL... other than the fact that nature is incompatible with humans who think they can play god, what does nature have to do with any of that? nothing.

Maybe some day they'll make a woman out of a "hank of hair and a piece o' bone".

And to carry that thought a step further, maybe someday we can go to a website and custom-order a woman from a series of drop-down menus?? Pick the features we want and go to the checkout page. To minimize costs and freight damage, we might even generate the goods on the spot with a 3D printer.

But picture a used woman sales lot on every street corner... "We tote the note" - hahahaha!

All things are possible, especially when the scientists involved have loosely-defined moral and ethical values.

All things are possible, especially when the scientists involved have loosely-defined moral and ethical values.

Scientists would not be the entrepreneurs making a killing off of these women. Scientists hardly ever determine how their discoveries are used, the free market does based on supply and demand. If there is a market for lab-created women then the people you should be attacking here are the people who create the demand that creates that market.

But you don't really know how anything works, science, politics, economics, or society.

But you don't really know how anything works, science, politics, economics, or society.

I probably know more than you think.

Take the AGW hoax as an example: I know the virtually all the data that I've seen is produced by biased "researchers", who benefit financially from their AGW efforts. Scams such as AGW are fairly simple and are not hard to spot - just follow the money.

ScooterG identified vaguely his association with an untestable belief system with

As a creationist, I would say that calling this "synthetic" is a misnomer. Truly synthetic would be creating life from raw elements off the periodic chart.

It all depends on where one accesses the 'permutation space' which for Carbon is approx 10E60.

Your comment is ludicrous, water is ubiquitous as are many other compounds in primitive atmospheres such as ammonia - interesting all our amino acids are derived from ammonia - which matches the early earth atmosphere...

Synthetic just means its constructed artificially, there is no observable or empirical difference between water made naturally or otherwise, there is lots of it in the solar system...

What sort of 'creationist' do you claim to be and on what BASIS do you arrive at such an odd static belief - religious or otherwise and how is this 'belief' communicated to you in the first place ?

ScooterG identified vaguely his association with an untestable belief system with

As a creationist, I would say that calling this "synthetic" is a misnomer. Truly synthetic would be creating life from raw elements off the periodic chart.

It all depends on where one accesses the 'permutation space' which for Carbon is approx 10E60.

Your comment is ludicrous, water is ubiquitous as are many other compounds in primitive atmospheres such as ammonia - interesting all our amino acids are derived from ammonia - which matches the early earth atmosphere...

Then take whatever inanimate objects you need and go build a living creature.

I dont see anything substantive in your reply except link to a 5 page diatribe.I offer that Science = "The Disciplined acquisition of knowledge", so in respect, the dialectic:-

Is ScooterG able to think independently when I asked this question

Are you unaware the earth is essentially a closed system, therefore burning a great deal of CO2 in a relatively short period of time creates a step change in environmental dynamics ?

Science shows quite definitively CO2 is a green house gas and over the last several decades humans have been responsible for a great deal of additional CO2.

I realise its so very hard for people to appreciate that such a huge amount of CO2 from the industry to support 7 or so billion people results in such a small rise in global temperatures and especially so given the massive heat capacity of the oceans.

Are you acquainted with the scientific understanding of 'specific heat' ?

What type of creationist do you claim to be since you brought the subject up ?

Are you unaware the earth is essentially a closed system, therefore burning a great deal of CO2 in a relatively short period of time creates a step change in environmental dynamics ? Science shows quite definitively CO2 is a green house gas and over the last several decades humans have been responsible for a great deal of additional CO2.

Are you able to prove it? And please don't bore us by citing biased research - after all, that's the crux of the entire AGW matter.

1. Opinion primarily, could be a claim, not an observation.2. Self contradictory, Science is based upon discipline, prejudice is not.3. Contingent upon level of supporting research4. " " preset bias5. " " understanding of linguistics & grammar6. " " best use of available intelligence...7. Implies mathematical equivalence, bad propagandist use of '='

Smarter to rewrite as:-

"Measurement data plus prejudice is mostly nonsense"

Biggest problem assessing AGW is complexity of climate models & there are many!

So start off with first principles or rather initial knowns.

The main proposition is:"Earths climate system is essentially closed".

So rather than arguing various models & provenance, isnt it best to appreciate a sensible starting point & examine that with some earnest focus, rationale(s) arise ?